PROJECT ABSTRACT Septic patients requiring 14 or more days of ICU care have been recently defined as chronically critically ill (CCI) patients. A subgroup of CCI patients develops persistent inflammation/immunosuppression and catabolism syndrome (PICS), and they have morbid long-term outcomes (Project #1). CCI patients with PICS often develop severe diaphragm and skeletal muscle atrophy and weakness. PICS patients also demonstrate diminished muscle mitochondrial function and accelerated protein catabolism. Muscle dysfunction in PICS is due to many factors including sarcopenia, sepsis/inflammation, proteolysis, apoptosis, and inactivity. Diaphragm weakness can delay patients' weaning from mechanical ventilation, and increase inflammation and the risk of nosocomial infection. Limb-muscle weakness prevents patients from reaching functional activity milestones, delaying their rehabilitation and return to normal function. Despite the seriousness of diaphragm weakness in CCI patients receiving mechanical ventilation, little is known about exercise strategies to treat this dysfunction. We also have limited knowledge about how strength training impacts inflammation, immunosuppression, and catabolism in CCI patients. In Project #4, we will conduct a Phase I/II randomized trial of specific inspiratory muscle strength training (IMST) for up to 28 days in 24 ventilated CCI patients to determine if they can respond to a training program that has previously shown to improve weaning outcome in chronically ventilated patients. Furthermore, because CCI patients also develop profound lower-extremity muscle weakness, for which little is known about the effectiveness of strength training, we propose to conduct a Phase I/II randomized trial of lower-extremity strength training in an additional 24 ventilated CCI patients for 28 days. Following training, muscle biopsies will be obtained from the quadriceps and contrasted between strength-trained and SHAM groups examining mitochondrial dysfunction, markers of anabolic and catabolic activity, and apoptosis. Both trials will also assess the effect of exercise on markers of inflammation, immunosuppression, and protein catabolism. Project #4's main functions will be the following: * Determine the effects of IMST on diaphragm strength in treated and control CCI patients. * Determine whether knee extension strengthening exercises induce changes in muscle properties including morphology, protein expression, and bioenergetics. * Determine the effects of knee extension strengthening exercises on the quadriceps muscle in CCI patients and on systemic inflammatory, immunosuppressive and catabolic markers. This project will further our understanding of how treating CCI-related muscle weakness with strength training can not only improve muscle function, but also potentially blunt the inflammation, immunosuppression, and catabolism of PICS.